Plymorphic forms of phenyl oxazolidinone derivatives

Abstract

The invention relates to phenyl oxazolidinone derivatives. More particularly, it relates to polymorphic forms of (S)-N-[[3-fluoro-4-[N-1[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride having the Formula I. Further, the invention relates to methods of using such compounds as antimicrobials, pharmaceutical compositions containing the novel polymorphic forms, and processes for the preparation of the polymorphic forms.

1 . A polymorph ‘Form A’ of(S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl)]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride having the following 10 most intense X-ray powder diffraction peaks: (2θ): 
 26.62, 26.20, 24.72, 21.94, 21.18, 20.60, 17.62, 16.84, 16.22, 14.74.    
     
     
         2 . The polymorph ‘Form A’ of(S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride using an infrared absorption spectrum in potassium bromide with absorption bands expressed in reciprocal centimeters at 3421; 3286; 2967; 1747; 1723; 1668; 1524; 1416; 1354; 1327; 1242; 1170; 1106; 1078; 1022;811 and 749.  
     
     
         3 . The polymorph ‘Form A’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride having a differential scanning calorimetry (DSC) endotherm at 211.9° C. (onset at 206.6° C.).  
     
     
         4 . A polymorph ‘Form B’ of(S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]phenyl}-2-oxo-5-oxazolidinyl]-methyl acetamide hydrochloride having the following X-ray powder diffraction pattern: (2θ): 
 15.9, 19.1, 20.2, 23.1, 25.7, 26.5, 28.5.    
     
     
         5 . The polymorph Form ‘B’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride characterized by an infrared absorption spectrum in potassium bromide having absorption bands expressed in reciprocal centimeters at 3423.2; 2386; 1747; 1654.3; 1519; 1425.9; 1356.2; 1239.2; 1022; 972.1; 811.7 and 750.2.  
     
     
         6 . The polymorph Form ‘B’ of(S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride having differential scanning calorimetry (DSC) endotherms at 154.9° C. (onset at 148.3° C.) and at 209.2° C. (onset at 207.5° C.).  
     
     
         7 . A process for preparing the polymorph ‘Form A’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl] acetamide hydrochloride, wherein the process comprises: 
 a) dissolving (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazlidinyl]methyl acetamide in ethanol;    b) adding ethanolic hydrochloric acid;    c) cooling and stirring the reaction mixture;    d) filtering and digesting the solid in ethanol;    e) cooling, filtering and drying the solid to produce polymorph ‘Form A’.    
     
     
         8 . The process of  claim 7  wherein the cooling of the solid in ethanol after digestion is carried out at a temperature of about 10° C.  
     
     
         9 . The process of  claim 7  wherein the drying of the product is carried out under vacuum at a temperature ranging from about 60-65° C.  
     
     
         10 . A process for preparing the polymorph ‘Form B’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride, wherein the process comprises: 
 a) dissolving (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidenyl]methyl acetamide in ethanol;    b) cooling the solution and adding ethanolic hydrochloric acid;    c) stirring the reaction mixture;    d) filtering the solid to produce polymorph ‘Form B’.    
     
     
         11 . The process of  claim 10  wherein the cooling is carried out at a temperature of about 20° C.  
     
     
         12 . A process for preparing the polymorph ‘Form A’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride, wherein the process comprises: 
 a) dissolving (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide in ethanol;    b) adding a mixture of hydrochloric acid in ethanol;    c) removing the solvent and digesting the residue in dichloromethane;    d) filtering and crystallizing the solid;    e) digesting the solid in ethanol;    f) cooling, filtering and drying the solid to produce polymorph ‘Form A’.    
     
     
         13 . The process of  claim 12  wherein the crystallization of the solid is carried out in a solvent selected from the group comprising of methanol and isopropyl alcohol.  
     
     
         14 . The process of  claim 12  wherein the cooling is carried out at a temperature of about 25-30° C.  
     
     
         15 . The process of  claim 12  wherein the drying of solid is carried out under vacuum at a temperature ranging from about 60-65° C.  
     
     
         16 . A process for preparing the polymorph ‘Form A’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride, wherein the process comprises: 
 a) dissolving (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)-methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide hydrochloride in de-mineralized water;    b) adding isopropyl alcohol;    c) stirring and filtering the solid;    d) drying the solid to produce polymorph ‘Form A’.    
     
     
         17 . The process of  claim 16  wherein the drying of solid is carried out under vacuum at a temperature of about 60° C.  
     
     
         18 . A process for preparing the polymorph ‘Form A’ of (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide hydrochloride, wherein the process comprises: 
 a) dissolving (S)-N-[[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)-methyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide hydrochloride in de-mineralized water;    b) adding ethanol;    c) stirring, cooling and filtering the solid;    d) drying the solid to produce polymorph ‘Form A’.    
     
     
         19 . The process of  claim 18  wherein the drying of solid is carried out under vacuum at a temperature of about 60° C.  
     
     
         20 . A pharmaceutical composition comprising a compound according to any one of the claims  1 ,  2 ,  3 ,  4 ,  5  or  6  and a pharmaceutically acceptable carrier.  
     
     
         21 . A method of treating or preventing microbial infections in a mammal comprising administering to the said mammal, a compound according to any one of the claims  1 ,  2 ,  3 ,  4 ,  5  or  6 .  
     
     
         22 . The method of treating or preventing microbial infections in a mammal comprising administering to the said mammal, a pharmaceutical composition according to  claim 20 .  
     
     
         23 . A method of treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to the said mammal, a therapeutically effective amount of a compound according to any one of the claims  1 ,  2 ,  3 ,  4 ,  5  or  6 .  
     
     
         24 . The method of treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to the said mammal, a therapeutically effective amount of a pharmaceutical composition according to  claim 20 .  
     
     
         25 . A method of treating or preventing catheter infections and foreign body or prosthesis infections in a mammal comprising administering to the said mammal, a therapeutically effective amount of a compound according to any one of the claims  1 ,  2 ,  3 ,  4 ,  5  or  6 .  
     
     
         26 . The method of treating or preventing catheter infections and foreign body or prosthesis infections in a mammal comprising administering to the said mammal, a therapeutically effective amount of a pharmaceutical composition according to  claim 20 .  
     
     
         27 . The method according to  claim 21  or  22  wherein the microbial infections are caused by gram positive and gram negative bacteria.  
     
     
         28 . The polymorph ‘Form A’ of  claim 1  having the following 20 most intense X-ray powder diffraction peaks: (2θ): 
 31.48, 28.60, 28.14, 26.62, 26.20, 24.72, 23.52, 22.84, 22.48, 21.94, 21.18, 20.60, 20.00, 19.74, 17.62, 16.22, 16.84, 14.74, 13.20, 12.86.